The interaction between four different microparticulate drug carriers and macrophages was investigated in vitro. The microparticles, consisting of crosslinked starch (1,4-α-D-glucan with 1,6-α-branches), dextran (1,6-α-D-glucan with 1,3-α-branches), lichenan (1,3-β-D-glucan), or mannan (1,6-α-D-mannan with 1,2-α- and 1,3-α-branches), were investigated for their macrophage stimulatory properties. Macrophage stimulation was assayed by the uptake of [14C]glucosamine and stimulatory indices were calculated. Microparticles made of crosslinked lichenan were most stimulatory, followed by the biologically inert mannan and dextran microparticles. Biodegradable starch microparticles were less stimulatory to the macrophages than the other microparticles. All microparticles were phagocytosed to the same extent and stimulated the macrophages to release oxygen radicals. Lichenan, mannan, and dextran microparticles induced morphological changes in the macrophages when given in nontoxic doses. No morphological changes were observed when the macrophages were exposed to starch microparticles or soluble polysaccharides.